Search Results (2,712)

Gonadotropin-Releasing Hormone receptors (GnRHRs) are overexpressed in several hormone-dependent malignancies, making them attractive molecular targets for selective anticancer drug delivery. Peptide–drug conjugates (PDCs) are a promising therapy for cancer and autoimmune diseases with high specificity and reduced toxicity. In this study, the three-dimensional structures of two previously synthesized mitoxantrone–GnRH conjugates, con3 and con7, were elucidated using high-resolution NMR spectroscopy in combination with molecular dynamics (MD) simulations. Complete ¹H and ¹³C resonance assignments were achieved in DMSO-d₆ through two-dimensional NMR experiments. NOESY-derived distance restraints were subsequently used to refine the conformational ensembles obtained from MD simulations performed in water and DMSO. Both conjugates exhibited compact bent conformations with a U-shaped peptide backbone. The mitoxantrone moiety is positioned close to the peptide backbone in water simulations and NMR-refined structures, while it is positioned farther away in DMSO, without affecting the orientation of key residues involved in GnRH receptor binding. Importantly, His², Trp³, and Arg⁸ remain solvent-exposed, whereas the disulfide bond is easily accessible to the solvent, consistent with the proposed drug release mechanism by the thioredoxin system. NMR-restrained molecular modeling confirmed the dominant conformational features predicted by the unconstrained theoretical simulations. Overall, these findings provide better structural understanding of the molecular organization of mitoxantrone–GnRH conjugates, highlighting key receptor-recognition residues and supporting both the proposed thioredoxin-mediated drug release mechanism and their previously reported biological properties. These insights may facilitate the rational design and optimization of improved GnRH peptide–drug conjugates for targeted therapy. Full article

Magnetothermally responsive nanocarriers represent a promising platform for spatio-temporally controlled drug delivery by combining alternating magnetic field (AMF)-induced heating with thermally triggered cargo release. Among the available architectures, magnetite-core/mesoporous-silica-shell (Fe₃O₄@mSiO₂) nanoparticles functionalized with thermoresponsive polymer gatekeepers are particularly attractive. These systems integrate a magnetic heat source, a mesoporous drug reservoir, and temperature-dependent control of pore accessibility. This review examines the fundamental principles of magnetic hyperthermia, including heat-generation mechanisms, specific absorption rate (SAR), intrinsic loss power (ILP), AMF parameters and safety, and the interplay between Néel and Brownian relaxation. It also critically discusses core–shell synthesis and architecture, drug-loading strategies, PNIPAM-, PNVCL-, and other LCST-type gatekeepers, and the physicochemical characterization required to validate the complete nanocarrier. Evidence for combined magnetic hyperthermia and chemotherapy is assessed together with hemocompatibility, immunogenicity, oxidative stress, biodistribution, degradation, long-term retention, and clearance. Although promising magnetothermal release and therapeutic effects have been reported, evidence remains dominated by in vitro studies, with limited in vivo validation. Current clinical experience concerns locally administered iron-oxide hyperthermia rather than complete thermoresponsive Fe₃O₄@mSiO₂ drug-delivery systems. Translation will require standardized magnetothermal and release testing, reproducible scale-up, validated sterilization and endotoxin control, component-resolved pharmacokinetics, and integrated development of the nanocarrier and AMF applicator. Full article

Wound management continues to represent a major global healthcare challenge, with the wound care market growing each year and a rising incidence of chronic wounds worldwide. Effective wound healing requires dressings that protect injured tissue, prevent infection, and actively modulate the wound microenvironment to promote tissue regeneration. In recent years, smart polymeric wound dressings have emerged as a functional, more advanced class of wound dressings, engineered from materials capable of responding to stimuli. Physically responsive systems include moisture-adaptive dressings that prevent wound dryness or maceration, pressure-sensitive dressings incorporating flexible capacitive sensors for high mechanical stress mapping, thermoresponsive dressings exploiting sol–gel transitions for temperature-controlled drug release, light-responsive dressings enabling photothermal and photodynamic therapy, and electro-responsive dressings integrating conductive polymers for self-powered electrical stimulation or closed-loop wound monitoring. Chemically responsive systems exploit endogenous biochemical signals, including pH shifts for wound monitoring, reactive oxygen species-cleavable bonds for on-demand drug release, and glucose-responsive platforms for autonomous glycemic regulation in diabetic wounds. Biologically responsive dressings use enzymatic triggers, such as matrix metalloproteinases, hyaluronidase, and bacterial proteases, to achieve autonomous drug delivery. Film-forming sprays further expand the versatility of smart polymeric dressings by enabling contactless application adaptable to irregular wound shapes. In this review, we summarize recent advances in the design, stimuli-responsive mechanisms, characterization methods, and therapeutic outcomes of smart polymeric dressings for wound treatment. Despite promising preclinical results, challenges related to clinical translation, regulatory standardization, and scalable production remain and must be addressed to facilitate widespread clinical adoption. Future directions include multi-stimuli responsive platforms, artificial intelligence-guided wound monitoring, bioprinting of specific dressings, and environmentally sustainable biomaterial design. Full article

Background/Objectives: The buccal mucosa offers a promising non-invasive route for systemic drug delivery, particularly for hydrophilic compounds like captopril (CAP), which exhibit low permeability and are subject to gastrointestinal instability and first-pass metabolism. This study aimed to develop and characterize captopril-loaded, chitosan-based mucoadhesive buccal films with different permeation enhancers and to evaluate their physicochemical properties, drug release, cytocompatibility, and in vitro transport across a TR146 buccal epithelial cell model. Methods: Films were prepared by the solvent-casting method using chitosan as the film-forming polymer. Different enhancers were investigated, including organic acid salts of chitosan (ascorbate, citrate, and lactate) and chemical permeation enhancers (sodium lauryl sulfate, polyethylene glycol 400, Span 20, and EDTA). Results: The resulting films exhibited acceptable thickness, moisture content, appropriate mechanical properties, and good mucoadhesive strength. In vitro dissolution studies demonstrated rapid CAP release, with >50% released within 15 min and near-complete release by 180 min across all formulations. Cytotoxicity assessment via a Neutral Red uptake assay in TR146 cells confirmed high cell viability (>81%) after 4 h of exposure, indicating good biocompatibility. In vitro permeation experiments revealed that films prepared with chitosan ascorbate and chitosan lactate enhanced CAP transport compared to other formulations, achieving the highest flux and apparent permeability coefficients. Conclusions: These findings demonstrate that chitosan ascorbate and lactate salts effectively improve the buccal permeability of captopril while maintaining good film properties and biocompatibility. This work highlights the potential of chitosan ascorbate- and lactate-based mucoadhesive films as an efficient platform for the buccal delivery of CAP. Full article

Poor aqueous solubility remains one of the most persistent challenges in pharmaceutical development, limiting clinical translation and requiring innovative formulation strategies; approximately 40% of newly discovered pharmaceutical compounds are affected, underscoring the scale of the problem. Emulsion-based delivery systems overcome this limitation by maintaining drugs in a dissolved state, increasing absorption surface area, and enabling controlled release; however, conventional emulsions face thermodynamic instability and coalescence challenges. Cellulose and nanocellulose—cellulose nanocrystals (CNCs), cellulose nanofibers (CNFs), and bacterial cellulose (BC)—have emerged as sustainable, biocompatible alternatives to synthetic surfactants for stabilizing emulsions via Pickering mechanisms involving irreversible adsorption of solid particles at the oil–water interface. This review synthesizes 142 references across eight application themes: fundamentals and history, emulsion templating, drug encapsulation, antimicrobial and pathogen applications, vaccine adjuvants, topical and transdermal delivery, commercial translation, and regulatory gaps. Rather than treating all sources equally, 37 primary studies are examined in depth through structured critical-appraisal tables organized by system type, goal, key result, and limitation; the remainder are synthesized at the pattern level. A key mechanistic distinction is identified between BC as a standalone biomedical material (used in wound dressings, tissue scaffolds, and drug delivery membranes) and BC as a source for Pickering-emulsion stabilizers after disintegration into nanocrystals or nanofibrils. The review’s overall assessment is that the fundamental materials science of cellulose Pickering emulsions is mature and consistent across sources, while the translational evidence, including in vivo confirmation of drug release performance, biofilm-relevant antimicrobial testing, standardized nanocellulose characterization, and up-to-date intellectual property mapping, remains the binding constraint on clinical and commercial adoption. Six specific, evidence-linked research priorities are identified to advance cellulose emulsions toward regulatory approval and clinical use. Full article

Nickel–titanium (NiTi) stents have been widely used for the palliative management of portal vein tumor thrombosis (PVTT) due to their excellent mechanical strength and biocompatibility. However, conventional NiTi implants are therapeutically passive and lack intrinsic antitumor activity, rendering them vulnerable to tumor ingrowth and subsequent restenosis. Electrical stimulation-mediated ablation offers a controllable physical strategy for local tumor clearance; however, the native TiO₂ passivation layer on the NiTi surface restricts its interfacial electroactivity. Electrochemical impedance spectroscopy revealed that the PPy coating significantly reduced the interfacial impedance of the NiTi substrate. After loading with sorafenib, NiTi−PPy−S maintained good electrochemical responsiveness and enabled voltage-dependent drug release characteristics. Under an applied potential of 0.9 V for 24 h, approximately 10.522 ± 0.295 μg/cm² of the loaded sorafenib was released mechanistically, whereas only 0.249 ± 0.171 μg/cm² was released through passive diffusion over the same period. The antitumor effect is closely associated with ES-triggered Ca²⁺ influx, mitochondrial Ca²⁺ overload, loss of mitochondrial membrane potential, and caspase-3-dependent apoptosis. These findings demonstrate that electro-responsive PPy can transform passive NiTi implants into active antitumor therapeutic interfaces, offering a promising strategy for developing multifunctional implants for PVTT treatment. Full article

In this study, alginate hydrogels (A) cross-linked with a mixture of calcium and europium ions (Ca+Eu)A were developed for the first time as potential carriers for the targeted delivery and sustained release of drugs to specific regions of the gastrointestinal tract. Comparative studies were conducted to investigate the effect of the cross-linking agent (Ca²⁺, Eu³⁺, or their mixture) on the physicochemical properties of alginate hydrogels and the release kinetics of metronidazole in media simulating different gastrointestinal environments. Rheological analysis demonstrated that (Ca+Eu)A hydrogels form mechanically robust, highly cross-linked networks. The hydrogels exhibited negligible swelling in an acidic medium (swelling ratio, SR ≈ 1–1.5 g/g); however, in PBS, calcium alginate (CaA) hydrogels swelled 7–8 times more (SR ≈ 42.5 g/g) than hydrogels cross-linked with Eu³⁺ ions or a Ca²⁺/Eu³⁺ mixture (SR = 5–8 g/g). Metronidazole was released 1.5–2 times faster from calcium-cross-linked hydrogels than from hydrogels cross-linked with Eu³⁺ ions or the mixed Ca²⁺/Eu³⁺ system, whereas (Ca+Eu)A hydrogels exhibited a more sustained and uniform release profile. These results demonstrate that the drug release kinetics can be tuned by adjusting the Ca²⁺/Eu³⁺ ratio during alginate cross-linking. Consequently, such hydrogels represent a promising platform for the targeted delivery and controlled release of therapeutic agents, particularly antibiotics, to specific regions of the gastrointestinal tract. Full article

Stimuli-responsive drug-delivery systems (SRDDS) have transformed precision medicine by enabling spatiotemporal control over therapeutic release, significantly reducing off-target toxicity while enhancing efficacy at the disease site. Naturally occurring polysaccharides, such as hyaluronic acid, chitosan, alginate, and dextran stand out as premier scaffolds for these “smart” nanoplatforms due to their inherent biocompatibility, biodegradability, and abundance of reactive sites for molecular engineering. This review explores the versatility of polysaccharide functionalization, detailing how the introduction of molecular “switches” allows these biopolymers to sense and respond to specific physiological triggers. We analyze the mechanisms behind acid–labile bonds for pH-triggered release, redox-sensitive bridges for intracellular delivery, and enzyme-cleavable sequences for bio-catalytic activation. By bridging the gap between molecular functionalization and clinical utility, these bio-responsive polysaccharide architectures enable integrated physiological monitoring and theranostic applications. This review highlights the impact of these advancements in overcoming biological barriers, providing a sophisticated blueprint for the next generation of nature-derived, “intelligent” biomaterials in cancer therapy. Full article

Circadian rhythms determine biological clocks that manage daily biological functions, including the sleep–wake rhythm, hormone release, and immune function. This can affect immune-mediated chronic inflammation in rheumatoid arthritis (RA), which leads to joint damage, pain, swelling, and morning stiffness. These clinical manifestations follow a distinct circadian rhythm because of the cyclic pattern of leukocyte movement, secretion of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α at night, and fluctuations in cortisol and melatonin levels. Despite the increasing amount of evidence showing that insufficient sleep and disruption of the biological clock may play a role in RA development through suppression of the immune response in macrophages and resorption processes in osteoclasts, the cause of this phenomenon is still under investigation. The present-day guidelines continue to endorse DMARDs as the basis of treatment, while studies are exploring the role of chronotherapy as an adjunctive method for alleviating symptoms and enhancing disease outcomes. In this review, we explore current knowledge regarding the links between the molecular basis of circadian biology and the pathogenesis of RA, highlight recent trends in immune and bone remodeling mechanisms, and discuss modern possibilities for using chronotherapy, precision medicine, and advanced drug-delivery methods based on circadian rhythms to create optimal treatment strategies for RA. Full article

Background: Photodynamic therapy (PDT) is a cancer treatment that combines a photosensitizer (PS), light, and oxygen to generate reactive oxygen species (ROS), leading to tumor cell death. PDT efficacy depends largely on PS accumulation within tumors, prompting the development of third-generation PSs and nanotechnology-based delivery systems. Among these, BODIPYs (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) are promising PSs due to their favorable photophysical properties, while liposomes improve drug delivery, cellular uptake, and sustained release profiles. This study describes the synthesis of two novel BODIPY derivatives differing in the position of a methyl ester group on the meso-phenyl ring, their incorporation into liposomes, and evaluation of PDT efficacy. Methods: Cellular uptake of BODIPY-loaded liposomes, intracellular ROS generation, apoptosis, necrosis, and lipid peroxidation were assessed by flow cytometry in colorectal and ovarian cancer cell lines. The antitumor activity of the liposomal formulations was further evaluated in both 2D and 3D models using MTT and clonogenic assays. The involvement of ferroptosis and necroptosis in PDT-induced cell death was also investigated. Results: Liposomal formulations significantly enhanced cellular uptake compared with free compounds. Following light activation, both formulations induced potent antitumor effects through multiple cell death mechanisms, including canonical and non-canonical pathways, and maintained strong efficacy in 3D tumor spheroids. Conclusions: Liposome-encapsulated BODIPYs represent promising PDT agents by improving cellular uptake and eliciting robust antitumor activity through complementary cell death mechanisms. Furthermore, the methyl ester substituent on the meso-phenyl ring provides a versatile platform for future conjugation with targeting ligands, supporting the development of third-generation, tumor-targeted photosensitizers and warranting further preclinical investigation. Full article

Efficient treatment of diabetic wounds (DW) remains a major clinical challenge worldwide owing to vascular insufficiency, multiple bacterial infections, and overactivation of pro-inflammatory M1 macrophages caused by hyperglycemia. The development of novel pharmaceutical agents with multiple biological functions is urgently needed. Coptis chinensis Franch. (CC) has been used to treat diabetes for thousands of years in China, but the curative effects and underlying mechanisms of CC in DW remain uncertain. Herein, a homogeneous heteropolysaccharide component, namely CCP, was isolated and purified from CC, which exhibited a molecular weight of 39,697 Da and was primarily composed of Glc, GalA, Ara, Gal, and Xyl. CCP has a light yellowish color and is distributed in a block shape with small surface granulations. In vitro experiments revealed that CCP dose-dependently mitigated high glucose-induced suppression of viability, migration, and tube formation in HUVECs. Meanwhile, CCP promotes the polarization of M1 macrophages toward the M2 phenotype to exert anti-inflammatory effects, while possessing certain antibacterial properties. In addition, a composite hydrogel system was successfully constructed by introducing sodium carboxymethyl cellulose and carbomer 940 for CCP delivery. The obtained hydrogels exhibited reasonable moisturizing, swelling, and drug release capacities, along with favorable rheological behaviors and certain antibacterial activity. More importantly, the in vivo wound healing model evaluation in diabetic rats demonstrated that CCP hydrogel dressings could effectively promote wound healing by reducing inflammation, accelerating collagen deposition, upregulating the expression of VEGF and key angiogenesis-related factors. In addition, composite hydrogels demonstrated excellent cytocompatibility and hemocompatibility, which holds great promise for clinical application in DW treatment. Full article

Local drug delivery increasingly relies on injectable hydrogels that form directly at the x‘administration site, among which light-cured systems are of particular interest: irradiation converts a liquid precursor into a depot and can trigger drug release with high spatiotemporal resolution. The aim of this critical narrative review is to systematize the key design elements of such systems and to assess their path toward the clinic. We analyze the mechanisms of photoactivation, the role of wavelength, the natural, synthetic, and hybrid polymer matrices together with their tuning parameters, and the photoinitiators. The clinical and preclinical experience in dentistry, ophthalmology, regenerative medicine, and oncology is then considered separately. Finally, we address standardization through the Quality by Design concept. We show that, despite an extensive preclinical base, no photocrosslinkable injectable depot for drug delivery has yet been approved, whereas photopolymerization itself and the photoinitiators employed are already accepted in the clinic in adjacent fields. We conclude that clinical translation is defined by three tractable tasks: qualifying photoinitiators for the injectable route of administration, overcoming the limited depth of light activation, and standardizing characterization on the basis of Quality by Design. Full article

Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by immune dysregulation, microbiota imbalance, and intestinal barrier damage. Unconjugated bilirubin (UCB) shows promise in treating UC due to its anti-inflammatory properties but is limited by poor solubility and potential toxicity. This study developed a chitosan-based controlled-release microsphere (CBMS) treatment to overcome these issues. CBMS utilizes the mucoadhesive properties of chitosan to achieve targeted, controlled UCB release in the colon, enhancing its stability and bioavailability. In a DSS-induced UC mouse model, CBMS alleviated clinical symptoms, reduced colon shortening, and improved histological outcomes, including reduced inflammation and enhanced mucosal repair. The mechanism involves CBMS retention in the intestinal lumen, UCB inactivation of digestive proteases, and restoration of microbiota balance, suppressing pro-inflammatory pathways. CBMS offers a promising new therapeutic strategy for UC and insights into polysaccharide-based drug delivery systems. Full article

Acetyl L-carnitine is an ester of the trimethylated amino acid L-carnitine with well-documented neuroprotective properties. Despite its ability to cross the blood–brain barrier, acetyl L-carnitine requires high and repeated doses to achieve and maintain therapeutic concentrations in the central nervous system. To overcome these limitations, nanotechnology-based delivery systems have emerged as a promising strategy to improve drug bioavailability, targeting, and therapeutic efficacy. In this study, we evaluated the efficacy of nanoparticle-based formulations of acetyl L-carnitine in comparison with its conventional bulk form using in vitro cultures of SH-SY5Y neuroblastoma cell line. The ALC nanoparticles were produced through an organic solvent-free mechanical ball milling process employing a planetary ball mill. The dimension and stability of the nanoparticles were analyzed by Dynamic Light Scattering and Thermogravimetric Analysis. The biological effects were evaluated using quantitative Real Time-Polymerase Chain Reaction, Enzyme-linked Immunosorbent Assay and immunofluorescence experiments. ALC nanoparticles, at low concentration of nanoparticles compared to the non-nanoparticle form, were able to decrease the alarmin S100B release, pro-inflammatory interleukin mRNA and protein expression as well as p65 activation, confirming their involvement in NF-κB pathway. Moreover, it was able to stimulate the nerve growth factor release and to increase intracellular Ca⁺⁺ levels, showing neuroprotective effects in addition to anti-inflammatory ones. Our findings allow us to highlight the therapeutic potential of ALC nanoparticles for neurological disorders, with the prospect of enhancing efficacy while reducing dosage and administration frequency. Full article

Cardiovascular diseases remain a major global health burden. Plant-derived extracellular vesicles (PDEVs) are increasingly being investigated as potential therapeutic and drug-delivery platforms for cardiovascular disease. PDEVs are natural nanovesicles carrying bioactive lipids, proteins, nucleic acids, and phytochemicals. Preclinical studies suggest that selected PDEV preparations may exert protective effects in cardiovascular disease-related models by modulating inflammation, oxidative stress, lipid metabolism, and endothelial repair. In experimental models, selected PDEVs have shown preliminary improvements in cargo stability, lesion accumulation, controlled release, and local retention through drug loading, surface ligand modification, responsive design, and integration with biomaterials. This review summarises the biogenesis, isolation, characterisation, and cardiovascular actions of PDEVs, with emphasis on their engineering and targeted delivery applications in atherosclerosis, myocardial infarction, ischaemia–reperfusion injury, vascular calcification, restenosis, and cardiotoxicity. Current challenges, including insufficient standardization, uncertain regulatory classification, unclear mechanisms, and limited pharmacokinetic and long-term safety data, are also discussed. Addressing these issues is essential for reliably evaluating the clinical translation potential of PDEVs. Full article